Methods are to be developed for the precise determination of the abundances of the stable isotopes carbon-13, deuterium, nitrogen-15, and oxygen-18 in samples of organic material. Differential isotope ratio mass spectrometry will be employed using a special instrument which measures ion current ratios by means of computer-controlled beam-switching, which is applicable to all the isotopes of interest, and which achieves a precision allowing measurement of natural isotopic abundance variations. The mass spectrometer requires less than 0.1 micromole of the element to be measured. Degradation techniques allowing extraction of all the hydrogen, carbon, nitrogen, or oxygen atoms from organic mixtures will be explored with the goal of achieving minimum sample sizes of 0.1 - 1.0 micromole for each of the elements mentioned. Applications of these techniques to the measurement of stable isotopic tracers in problems of drug metabolism and metabolic diseases will be undertaken.